Heavy metals in the human environment may cause major health problems. It is the long term objective of the work proposed here to study how these metals cross cell membranes to enter the body and the cells of sensitive target organs. In the non-industrial environment, the major source of the human body burden of heavy metals is ingestion through food and water; the problem with metal absorption resolves itself therefore into the question of how these compounds cross the intestinal barrier. This process will be studied in four different systems: 1) In the living rat; here a jejunal segment is isolated in situ and perfused through the lumen. Rates of disappearance from the lumen and appearance in portal venous blood are monitored to determine the kinetics of uptake. 2) Step 1 of absorption, reaction of metals with brush border membranes, will be studied with everted sacs of rat jejunum. 3) Purified brush border membrane preparations; such vesicles will be useful for the study both of metal movement across membranes, as well as the toxic effects of these metals on other membrane transport functions. 4) Artificial lipid membranes (liposomes); in each case the metals of primary interest are cadmium, mercury and nickel. In the occupational environment, or for heavy smokers, the mechanism of pulmonary metal uptake becomes important. This will be analyzed with sheets of epithelium isolated from the dog trachea, and with tight sheets of alveolar epithelial cells grown in culture; the species of Cd usually inhaled (CdO) is sufficiently soluble to permit such studies. At least in the mature intestine, uptake of metals at low concentrations involves primarily transcellular pathways. The hypothesis will be tested that the faster rate of metal uptake across pulmonary epithelium and by the neonatal gut than by mature intestine may be related to the existence of paracellular pathways. The role of intracellular trapping of the metals in determining rates of uptake will also be studied. An additional system which may prove useful in the study of metal membrane interaction is the mammalian red cell ghost.